The interaction between donor and recipient cells after transplantation has received great attention in an attempt to identify the basis of rejection and graft-versus-host disease (1-5). Cell migration from the allograft to the recipient results in systemic chimerism (6-8), and cell migration from the host to the transplanted organ results in chimerism of the organ (9, 10). Chimerism can be detected easily after sex-mismatched organ transplantation with FISH for the Y-chromosome (11-13) and several studies on cardiac chimerism have provided consistent results concerning the migration of progenitor cells (PCs) from the host to the graft (14-26). The sex-mismatched transplants make it possible to document and evaluate quantitatively a process that is part of cardiac homeostasis but it is otherwise not measurable in humans (27). After homing, host PCs undergo replication and differentiation, generating mature myocytes and vascular structures in the transplanted heart (14). Although there is little disagreement among authors in terms of the occurrence of this phenomenon, the magnitude of cardiac chimerism varies significantly in different reports (14-27). This discrepancy involves mostly ventricular myocytes and to a much lesser extent coronary vessels. For myocytes, the published values range from as high as 18% (14) to as low as 0.02% (15). Conversely, levels of endothelial cell chimerism and vessel formation have been shown to involve up to 22% of the coronary circulation (14, 25). In spite of these differences which previously have been discussed (27-31), the regenerated cardiomyocytes and coronary arterioles together with capillary profiles have normal morphology and are distributed predominantly in areas of intact donor myocardium (14). These data provide evidence that adult PCs contribute to the formation of solid-organ tissue cells (32-36), but leave unanswered the question whether the migrating cells arise from precursors in the atrial remnants of the recipient's heart or translocate from the recipient's bone marrow through the circulation to the transplanted organ (37).
After the first year, chronic loss of graft function (71) is the predominant cause of mortality in cardiac transplant patients (72). Inflammation and immune-mediated reactions (73) are responsible for the reduced sensitivity of myocytes to catecholamines, alterations in surface receptors, defects in ion-channels and depressed contractility (74, 75). Graft dysfunction is characterized by changes in the coronary arteries by a process termed cardiac allograft vasculopathy (CAV) (76). Although a causal relationship between reduced graft function and CAV remains to be demonstrated, the progressive occlusion of coronary vessels and ischemic myocardial damage are the critical mechanisms of graft failure (77-81). Several risk factors for CAV have been identified; they include systemic hypertension, body mass index, advanced donor age and number of rejection episodes (82-90). CAV inexorably leads to a chronic ischemic myopathy and death (91); 75% of transplant patients suffer from CAV one year following surgery (92, 93). Histologically, four etiologic factors have been considered: (a) intimal thickening mediated by migration of smooth muscle cells and/or proliferation of resident or migratory smooth muscle cells (94, 95); (b) infiltration of the intima by leukocytes recruited in response to injury or inflammation (96, 97); (c) accumulation of T lymphocytes and macrophages which generate a peri-vascular cuffing, local injury and irreversible damage, commonly defined as constrictive vascular remodeling (98-103); and (d) dynamic reduction in vessel diameter sustained by abnormalities in vasoconstriction and dilation (104-107). CAV differs from typical atherosclerotic lesions (108). With CAV, lesions are concentric and diffuse rather than eccentric and focal and extend beyond the large arteries reaching the penetrating smaller ramifications. Because of its diffuse distribution, CAV cannot be corrected with bypass surgery, angioplasty or stenting (72). In some cases, both types of lesions are present.
The cause of graft coronary artery disease remains elusive although immune and non-immune mechanisms have been implicated (70, 109). Controversy exists as to the origin of the proliferating cells present in CAV (110). It has been proposed that thickening of the intima is dictated by accumulation of recipient cells which derive from a pool of circulating PCs that differentiate locally into endothelial cells (ECs) and smooth muscle cells (SMCs) (111). Endothelial progenitor cells (EPCs) from the recipient may home to the intima and differentiate into endothelial-like cells (112-118) contributing to the vascular lesion. Similarly, SMC precursors could be recruited from the circulation and participate in vessel pathology (119-124). The results of cardiac chimerism in humans, however, question the negative effects of PCs of recipient origin (14, 15, 19, 20, 23, 25). There is general agreement that these cells contribute minimally to CAV and the formed coronary vasculature is structurally intact with no signs of atherosclerosis. The opposite view is supported by animal studies in which the orthotopic aorta allograft has been employed (117, 125, 126). This model has limitations; the aorta is structurally different from the coronary arteries and its intramural branches (127-130). Most importantly, medial necrosis is present in the orthotopic aorta allograft (125, 126, 131-133) while it is never observed in human CAV. These differences raise questions on the appropriateness of this model for graft vascular disease. At present, a few effective pharmacological therapies have been applied to the treatment of CAV. The HMG-CoA reductase inhibitors and the cell cycle inhibitor rapamycin reduce neointimal proliferation, myocardial infarction, the need for revascularization and death (134, 135). These therapies are extremely valuable but only delay the progression of CAV in the transplanted heart. Cell therapy with the formation of coronary vessels (47, 48, 51-53, 56, 57, 59, 64, 65) may increase coronary blood flow (CBF), decrease coronary resistance and enhance tissue oxygenation (136). The problem in need of resolution involves the identification and characterization of PCs that can form large conductive coronary arteries and their distal branches together with a large quantity of cardiomyocytes (59, 64, 137).